Moselio Schaechter

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« E. coli Cells Face FACS and Get Back into Shape | Main | TWiM #55: In the Copper Room »

April 25, 2013

A Good Defense Is Worth Stealing

by Merry Youle

Add phage ICP1 to the list. Source.

One widely-used tactic for defense against phage and other mobile genetic elements is to deploy a CRISPR-Cas system (click here and here) to recognize and chop them into pieces. Based on sequenced genomes, 60% of Bacteria and 90% of Archaea have the wherewithal to dispatch invaders this way. But phages also have to protect themselves against enemies, including other mobile elements. Knowing a good thing when they see it—and they have seen it from the receiving end often—some phages have stolen the entire CRISPR-Cas structure and use it to inactivate genetic elements that would interfere with their replication.

What sorts of genetic elements challenge phage supremacy? Some bacteria harbor chromosomal islands that, like prophages, excise and replicate when induced by cellular stress or damage. When phage infection is what triggers the activation, the island is classified as a PICI, a phage-inducible chromosomal island. The ungrateful PICI sometimes then proceeds to interfere with phage replication. One subset of these PICIs includes the SaPIs, Staphylococcus aureus pathogenicity islands, that I introduced here and wrote more about here.

Researchers observed that a PICI-like element (PLE) in Vibrio cholerae is activated by infection by a vibriophage (ICP1, here called simply the phage). PLE then blocks phage replication by some unknown mechanism. But this phage fights back with its own CRISPR-Cas system. Although CRISPR loci and Cas genes had been detected earlier in phage genomes and metagenomes, this paper is the first to document phage survival courtesy of a fully functional, phage-encoded CRISPR-Cas apparatus. For an introduction to CRISPRs, I again refer you to my earlier posts here and here. Briefly, a functioning bacterial CRISPR locus contains short sequences (spacers) that were acquired from the DNA of some invading genetic element, usually a phage or a plasmid. The RNA transcripts from the CRISPR region are processed into short CRISPR-RNAs, one per spacer. Each CRISPR-RNA recognizes the invader from which the spacer came and targets it for destruction by the Cas nucleases. With this vibriophage, it is the phage “invader” that carries the CRISPR and uses it to attack a mobile element resident in the host chromosome.

EM of V. cholerae phage ICP1, a myophage isolated from stool samples from cholera patients. Bar = 100 nm. Source.

The CRISPR locus of the vibriophage investigated here has two spacers that are identical to different regions within the PLE element in the host chromosome. Either one of those spacers is sufficient to protect the phage. However, if the perfect match between that spacer and the PLE is disrupted by mutations in either sequence, the PLE wins and the phage cannot replicate. But there is an adaptive dimension to CRISPR-Cas systems in Bacteria and Archaea. When challenged by a new invader, one never encountered before, these organisms acquire a new spacer from that element, add it to their existing CRISPR locus, and then use it to defend against that same invader. Is this phage as adept? Further experiments demonstrated that this vibriophage can indeed acquire new spacers when needed. The proof? I wrote above that phage without a PLE-matching spacer could not replicate in a host carrying the PLE, but in actuality a few “phage escape mutants” can (efficiency of plaquing could be as high as 3.5 × 10–5). When ten such escapees were sequenced, all ten had a new spacer added to their CRISPR locus, a spacer targeting the PLE.

In some parts of the world, these V. cholerae phage are a recognized ally, helping to control cholera outbreaks as they go about their daily routine of slaughtering bacteria. From our point of view, the PLE is a villain in cahoots with its V. cholerae host, providing its host with immunity against phage infection. Enlisting these vibriophages in our defense might help prevent cholera. With billions of years experience, the ingenious phages are a seemingly endless source of strategies that are, in turn, worth stealing.

Seed KD, Lazinski DW, Calderwood SB, & Camilli A (2013). A bacteriophage encodes its own CRISPR/Cas adaptive response to evade host innate immunity. Nature, 494 (7438), 489-91 PMID: 23446421


Bacteria and archaea have evolved various defense and regulatory mechanisms allowing them to react to various stressful situations caused by the environment, such as a virus attack. The recently discovered versatile CRISPR-Cas functions as a prokaryotic immune system. This system confers resistance to exogenous genetic elements such as plasmids and phages by providing a form of acquired immunity. The CRISPR Cas system has two novel features that allows the host to specifically incorporate short sequences from invading genetic elements such as a virus or plasmid into a region of its genome that is distinguished by clustered regularly interspaced short palindromic repeats (CRISPRs). Next, these sequences are transcribed and precisely processed into small RNAs to guide a multifunctional protein complex (Cas proteins) to recognize and cleave incoming foreign genetic material. This CRISPR Cas system is thought to be an adaptive immunity system which uses a library of small noncoding RNAs as a powerful weapon against fast-evolving viruses and is also used as a regulatory system by the host cells.

Thanks for sharing such a nice article. i love your writing. your idea is mind blowing that's why i would like to appreciate your work.

CRISPRs are constantly surprising us!

My biggest question was how does PLE prevent phage infection? Quite curious!

Crazy how something so beneficial to one part of the world's population can be so harmful to another portion. Although mostly beyond my comprehension great reading!

Thanks for the article but I wouldn't condone stealing of anything.

Thanks for sharing, it is well told, their contribution is appreciated!

Stealing strategies from such organisms can let us cure things, but also it can supose a big danger. We have to be careful.

Very nice post. Thank you for sharing information

Defence is the main on which wars are fought in the past.

Phage therapy is the therapeutic use of bacteriophages to treat pathogenic bacterial infections. Although extensively used and developed mainly in former Soviet Union countries circa 1920, the treatment is not approved in countries other than Russia and Georgia. Phage therapy has many potential applications in human medicine as well as dentistry, veterinary science, and agriculture.

Good day! This is my 1st comment here so I just wanted to give a quick shout out and tell you I genuinely enjoy reading your blog posts. Can you suggest any other blogs/websites/forums that go over the same subjects? Thanks for your time!

One of the most pertinent questions still remains

When will Phage Therapy reach countries other than Russia and Germany?

With regards to "I wrote above that phage without a PLE-matching spacer could not replicate in a host carrying the PLE", can you explain in a bit more detail please?

Merry replies: The PLE interferes with phage replication unless the phage has an effective defense against that particular PLE. It is not known exactly how the PLE interferes, but it can and does. The way the phage defends itself is by using its stolen CRISPR system. CRISPRs are effective against genetic elements such as PLEs if and only if the CRISPR has learned to recognize that element as a bad guy who should be destroyed. That's where the spacer sequence comes into the picture. When that phage encounters a PLE it is usually defeated. That's why I wrote that the phage cannot replicate in a host with a PLE. But a few phages out of a million do survive AND add a bit of the PLE DNA sequence to their own phage chromosome as a new spacer within the CRISPR locus. Then the next time one of these phages encounters the PLE, it uses that spacer as part of its mechanism to recognize and destroy the PLE. With the spacer, the phage wins; without the matching spacer it usually loses.

Natural defense system of body is good to surmount the foreign harmful elements. However, CRISPR-Cas system is also good to overcome the different fragile organisms that could create problem in human body.

Thanks for sharing such a nice article (",)

great article, thanks for sharing

Thanks for sharing such a nice article. i love your writing. your idea is mind blowing that's why i would like to appreciate your work.

CRISPRs are constantly surprising us!

My biggest question was how does PLE prevent phage infection? Quite curious!

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